11-1225711-A-G

Position:

• chr11-1225711-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002458.3(MUC5B):​c.101A>G​(p.Glu34Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,603,608 control chromosomes in the GnomAD database, including 47,266 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (5769 hom., cov: 32)
  • Exomes 𝑓: 0.23 (41497 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.379

Genes affected

MUC5B (HGNC:7516): (mucin 5B, oligomeric mucus/gel-forming) This gene encodes a member of the mucin family of proteins, which are highly glycosylated macromolecular components of mucus secretions. This family member is the major gel-forming mucin in mucus. It is a major contributor to the lubricating and viscoelastic properties of whole saliva, normal lung mucus and cervical mucus. This gene has been found to be up-regulated in some human diseases, including sinus mucosa of chronic rhinosinusitis (CRS), CRS with nasal polyposis, chronic obstructive pulmonary disease (COPD) and H. pylori-associated gastric disease, and it may be involved in the pathogenesis of these diseases. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.632141E-4).
• BP6: Variant 11-1225711-A-G is Benign according to our data. Variant chr11-1225711-A-G is described in ClinVar as [Benign]. Clinvar id is 163990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC5B	NM_002458.3	c.101A>G	p.Glu34Gly	missense_variant	2/49	ENST00000529681.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC5B	ENST00000529681.5	c.101A>G	p.Glu34Gly	missense_variant	2/49	5	NM_002458.3	P1
MUC5B	ENST00000525715.5	n.159A>G		non_coding_transcript_exon_variant	2/26	1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40760 AN: 151488 Hom.: 5757 Cov.: 32

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.265

GnomAD3 exomes AF: 0.263 AC: 61220 AN: 233150 Hom.: 8560 AF XY: 0.262 AC XY: 33190 AN XY: 126784

Gnomad AFR exome AF: 0.330

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.424

Gnomad SAS exome AF: 0.295

Gnomad FIN exome AF: 0.361

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.249

GnomAD4 exome AF: 0.231 AC: 335568 AN: 1452004 Hom.: 41497 Cov.: 33 AF XY: 0.232 AC XY: 167441 AN XY: 721394

Gnomad4 AFR exome AF: 0.338

Gnomad4 AMR exome AF: 0.235

Gnomad4 ASJ exome AF: 0.253

Gnomad4 EAS exome AF: 0.484

Gnomad4 SAS exome AF: 0.292

Gnomad4 FIN exome AF: 0.355

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.243

GnomAD4 genome AF: 0.269 AC: 40809 AN: 151604 Hom.: 5769 Cov.: 32 AF XY: 0.277 AC XY: 20500 AN XY: 74060

Gnomad4 AFR AF: 0.331

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.256

Gnomad4 EAS AF: 0.428

Gnomad4 SAS AF: 0.297

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.210

Gnomad4 OTH AF: 0.266

Alfa AF: 0.225 Hom.: 6867

Bravo AF: 0.263

TwinsUK AF: 0.202 AC: 748

ALSPAC AF: 0.213 AC: 819

ESP6500AA AF: 0.296 AC: 1174

ESP6500EA AF: 0.205 AC: 1699

ExAC AF: 0.255 AC: 30679

Asia WGS AF: 0.377 AC: 1313 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Glu34Gly in exon 2 of MUC5B: This variant is not expected to have clinical signi ficance because it has been identified in 29.6% (1174/3972) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs2672785). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.3
DANN	Benign	0.71
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.00026	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.037
Sift	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.015
ClinPred		0.00030	T
GERP RS		0.033
Varity_R		0.019
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2672785; hg19: chr11-1246941;